A diversity of approaches to address the challenge of drug-resistance in malaria

Biotechnology Unit, University of Buea. PO Box 63 Buea, South West Region, Cameroon

Corresponding Author:

Denis Zofou
Biotechnology Unit, University of Buea. PO Box 63 Buea
South West Region, Cameroon
Tel: 237-7718 3510
E-mail: zofden@yahoo.com

Received date: November 01, 2011; Accepted date: November 16, 2011; Published date: November 18, 2011

Citation: Zofou D (2011) A diversity of approaches to address the challenge of drug-resistance in malaria. J Biotechnol Biomaterial 1:e108. doi:10.4172/2155-952X.1000e108

Copyright: © 2011 Zofou D. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

For several decades, the phenomenon of drug resistance has remained the greatest challenge to malaria control, and it is part of the obstacles that sapped the dream of seeing malaria eradicated in the years 1970s. So far, resistance has been fully established in three of the five Plasmodium species responsible for human malaria (P. falciparum, P vivax and P. malariae). By WHO “drug resistance” is defined as “the ability of a parasite strain to survive or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the tolerance of the subject.” This definition originated in 1967 was later modified by adding that “the form of the drug active against the parasite must be able to gain access to the parasite or the infected erythrocyte for the duration of the time necessary for its normal action”. Cross resistance on the other hand is the simultaneous occurrence of resistance of the same parasite strain to two of more drugs belonging to the same drug family or exerting similar modes of action. Treatment failure is defined as “an inability to clear malarial parasitaemia or resolve clinical symptoms despite administration of an antimalarial medicine” [1]. Factors such as incorrect dosage, individual variations, host’s immune system, poor compliance in respect of the dose and duration of the treatment can equally lead to treatment failure, unlike drug-resistance which is an intrinsic property of the drug concerned. Malaria drug-resistance has led to enormous consequences including worsening of disease burden (increase mortality and morbidity), increased economic cost (cost of new drugs, increased socio-economical burden), and changes of disease management policies. Drug-resistance occurs as phenotype of mutation affecting parasite genome conferring evasion from drug targeting through any of the following mechanisms: drug inactivation or modification, active efflux, alterations in the primary site of action, alteration of metabolic pathway. Given the fact that the mutations are not deleterious to the survival or reproduction of the parasite, drug pressure will remove susceptible parasites while resistant parasites survive. Single malaria isolates have been found to be made up of heterogeneous populations of parasites lines with widely varying drug response characteristics, from highly resistant to completely sensitive [2,3]. Similarly, within a geographical area, malaria infections demonstrate a range of drug susceptibility.

For several decades, the phenomenon of drug resistance has remained the greatest challenge to malaria control, and it is part of the obstacles that sapped the dream of seeing malaria eradicated in the years 1970s. So far, resistance has been fully established in three of the five Plasmodium species responsible for human malaria (P. falciparum, P vivax and P. malariae). By WHO “drug resistance” is defined as “the ability of a parasite strain to survive or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the tolerance of the subject.” This definition originated in 1967 was later modified by adding that “the form of the drug active against the parasite must be able to gain access to the parasite or the infected erythrocyte for the duration of the time necessary for its normal action”. Cross resistance on the other hand is the simultaneous occurrence of resistance of the same parasite strain to two of more drugs belonging to the same drug family or exerting similar modes of action. Treatment failure is defined as “an inability to clear malarial parasitaemia or resolve clinical symptoms despite administration of an antimalarial medicine” [1]. Factors such as incorrect dosage, individual variations, host’s immune system, poor compliance in respect of the dose and duration of the treatment can equally lead to treatment failure, unlike drug-resistance which is an intrinsic property of the drug concerned. Malaria drug-resistance has led to enormous consequences including worsening of disease burden (increase mortality and morbidity), increased economic cost (cost of new drugs, increased socio-economical burden), and changes of disease management policies. Drug-resistance occurs as phenotype of mutation affecting parasite genome conferring evasion from drug targeting through any of the following mechanisms: drug inactivation or modification, active efflux, alterations in the primary site of action, alteration of metabolic pathway. Given the fact that the mutations are not deleterious to the survival or reproduction of the parasite, drug pressure will remove susceptible parasites while resistant parasites survive. Single malaria isolates have been found to be made up of heterogeneous populations of parasites lines with widely varying drug response characteristics, from highly resistant to completely sensitive [2,3]. Similarly, within a geographical area, malaria infections demonstrate a range of drug susceptibility. Over time, resistance becomes established in the population and can be very stable and persisting long after specific drug pressure is removed [2]. But when the particular drug stops being used, in a long run the resistance could be reversed. Numerous factors have been identified to influence drug-resistance [1]: (a) the intrinsic frequency with which the genetic changes occur; (b) the degree of resistance conferred by the genetic change; (c) the “fitness cost” of the resistance mechanism; (d) the proportion of all transmissible infectious agents exposed to the drug (exposure pressure); (e) the number of parasites exposed to the drug; (f) the concentration of drug to which the parasite are exposed; (g) the pharmacokinetics and pharmacodynamics of the antimalarial medicine; (h) individual (dosing, duration, compliance) and community (quality, availability, distribution) patterns of drug use; (i) the immunity profile of the community and the individual; (j) the simultaneous presence of other antimalarial drugs or substances in the blood to which the parasite is not resistant; and (k) the transmission intensity.

Drug-resistance has been documented for almost all antimalarials in current use, including old drugs like Quinine and the newly introduced artemisinins. For more than a decade, artemisinins and its derivatives have been the most widely used antimalarial drugs in endemic countries because of their high efficacy against multidrug-resistant strains of P. falciparum. ACTs have considerably contributed to reduce malaria burden. However, the recent emergence of artemisinin-resistant P. falciparum parasites in Western Cambodia-Thailand border is a serious alarming discovery for malariologists [1,4,5]. Mutations in several candidate genes have been postulated to confer Artemisinins - resistance. Working with laboratory strains and field isolates in vitro [6] showed that parasites can tolerate increasing concentrations of artemisinin drugs by amplifying the pfmdr1 gene.

The emergence and spread of resistance to all the anti-malarial drugs including Artemisinin-based combinations is a clear indication that there is an urgent need to discover new antimalarials. Many different approaches are followed in malaria drug discovery and development enterprise: (i) Optimization of therapy with existing agents, (ii) Development of analogs of existing agents, (iii) Compounds active against other diseases, (iv) Drug resistance reversers and (v) Rational drug design.

(i) Optimization of therapy with existing agents

Designing new dosing regiments or combining individual drugs with different mechanisms of actions is likely to optimize the antimalarial activity. This approach was suggested by WHO as a major means of combating resistance against monotherapy regiments since the late 1990s [7]. The combination can be done either between older drugs (atovaquone/proguanil, dapsone/chlorproguanil, amodiaquine/sulfadoxine/ pyrimethamine) or include new drugs (ACTs). The use of combination therapy offers two potential advantages. Firstly the combination improves the activity of the drugs, provided there is additivity or ideally the synergistic effects between partner drugs. Secondly, the use of combined drugs delays the appearance of drug resistance. An ideal antimalarial drug combination should be made up of a short-acting, highly potent compound and a longer-acting agent, both of which are still free of resistance. However, such a drug regimen does not exist, as resistance has been observed against all currently used antimalarials.

(ii) Development of analogs of existing agents

A second approach in malaria drug discovery goes from the knowledge of the chemistry of older drugs. An identification of the different functional groups of the active molecules can permit selection or synthesis of analogs which are further screened against parasites. The knowledge of mechanisms of action of the template drugs may not be required in this approach. Through such an approach, many antimalarials were developed; for example, chloroquine, primaquine and mefloquine from quinine [8].

(iii) Compounds active against other diseases

The third approach in malaria drug discovery goes from drugs previously used against other diseases, based either on similarity of the parasites targeted, or a random screening against malaria parasite. antifolates, tetracycline, doxicycline and other antibiotics, commonly known for their use against various bacterial infections, were later developed as antimalarials.

(iv) Drug resistance reversers

Combining previously effective agents with compounds that reverse parasite resistance to these agents offers another approach to malaria chemotherapy. This approach has led to development of drug combinations like chloroquine/verapamil that was shown to be effective against chloroquine resistant strains of P. falciparum [8].

(v) Natural products

Natural products have been a good source of lead compounds for drug development. A good example against malaria is Quinine, isolated from Cinchona bark, which was used as a template for the synthesis of Chloroquine and Mefloquine. More recently, Artemisinin isolated from the Chinese plant Artemisia annua, has been used successfully against CQ-resistant P. falciparum strains [9]. The natural products from diverse sources (plants, marine flora and microorganisms) may be chosen and screened at random or the source-materials may be selected based on previous knowledge (ethno-botanical or ethno-pharmacological surveys) of their use in the communities. Crude extracts prepared using suitable solvents are tested and undergo bioassay-guided fractionation towards detection and isolation of potential active pure ingredients. But the entire molecules cassette of the plant parts can be isolated and randomly tested against different parasite lines in the search of potential active compounds.

However, the conventional drug development is a slow and costly process which may require up to 15 years and up to US $ 900 million per new approved drug [10,11] and the finished products are often unavailable and unaffordable to the poorest patients in remote area, unless heavy subsidization schemes are put in place. In contrast the parallel development of standardized phytomedicines can be done more cheaply, faster, and more sustainably for remote areas. The concept of “reverse pharmacology” was coined in India to develop pharmaceutical products from traditional medicines, and was also implemented by Chinese in the 1950s. The first step was to select remedies for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment; and the last step to identify active compounds which can be used as markers for standardization and quality control. This innovative approach led to development of a new antimalarial phytomedicine from the Argemone mexicana aerial part decoction which is in the progress of being approved by the Malian regulatory authorities. Other antimalarial phytomedicines have already been developed and approved in many African countries [11]. These include Cochlospermum planchonii root decoction (Burkina Faso), Cryptolepis sanguinolenta root infusion (Ghana), Anemed^® Artemesia annua leaf infusion (Democratic Republic of Congo).

(vi) Rational drug design

This approach is certainly the latest and the most innovative one for chemotherapy, and consists of identifying potential drug targets through a metacomparison of the parasite metabolism to the one of the host. For several reasons, plasmodial proteins are tedious to characterise structurally using traditional physical approaches. Luckily, some of these problems can be overcome using in silico approaches. Mainly, homology modelling with specific focus on unique aspects of malaria proteins including low level of similarity with the host homolog, and the presence of parasite-specific inserts or features is addressed. Once a detailed description of the drug target is available, in silico approaches to the specific design of an inhibitory drug thereof becomes invaluable as an economic and rational alternative to chemical library screening [12]. Known molecules either synthesized or isolated from plants can equally be used in molecular docking. Best fitted molecules designed in silico are then synthesized and/or screened physically against their molecular targets or the whole-organism. The rational drug discovery approach has the advantage of preventing waste of resources, although some sophisticated technological tools may be required.

It is reasonably hopped that combining these major approaches is likely to generate batteries of new drug candidates that are necessary to face the recurrent challenge of drug resistance especially in malaria. However the discovery of new drugs for a disease like malaria (which affects more populations of the poorest areas of the world) is unrealistic for a pharmaceutical company or institute acting alone. A present, the research costs alone for a single drug candidate ready to enter clinical trial are in the order of US$20million. To face this permanent challenge, a number of non profit organisations today foster the efforts of individual researchers and companies through both technical and financial assistance. Some of these are the WHO/World Bank/UNICEF/ UNDP Special Programme for Training and Research in Tropical Diseases (TDR), the Medicines for Malaria Venture (MMV), Drugs for Neglected Diseases Initiative (DNDi), Multilateral Initiative on Malaria (MIM), African Malaria Network Trust (AMANET) and the African Network for Drug and Diagnosis Innovation (ANDI).

Finally the role of Open Access journals in this process should not be undermined. Unlike most scientific researches which are seriously limited by expensive paywalls, articles published in Open Access journals are made available to the world scientific community through online publishing systems free of charge. Like for all OMICS journals, abstracts and full texts accepted by the Journal of Biotechnology and Biomaterials (JBTBM) are freely accessible to everyone immediately after publication from the publisher website, but also through DOAJ, EBSCO, INDEX COPERNICUS, Scientific Commons and Google Scholar. The terms of the Creative Commons Attribution License to which JBTBM adheres permits anyone to copy, distribute, transmit and adapt the work, provided the original work and source is appropriately cited. This approach makes JBTBM and other OMICS journals a free, available and easily accessed source of information especially for scientists working with limited resources in developing countries.

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